title: Pathogenomic inference of virulence-associated genes in Leptospira interrogans.
abstract: Leptospirosis is a globally important, neglected zoonotic infection caused by spirochetes of the genus Leptospira. Since genetic transformation remains technically limited for pathogenic Leptospira, a systems biology pathogenomic approach was used to infer leptospiral virulence genes by whole genome comparison of culture-attenuated Leptospira interrogans serovar Lai with its virulent, isogenic parent. Among the 11 pathogen-specific protein-coding genes in which non-synonymous mutations were found, a putative soluble adenylate cyclase with host cell cAMP-elevating activity, and two members of a previously unstudied ∼15 member paralogous gene family of unknown function were identified. This gene family was also uniquely found in the alpha-proteobacteria Bartonella bacilliformis and Bartonella australis that are geographically restricted to the Andes and Australia, respectively. How the pathogenic Leptospira and these two Bartonella species came to share this expanded gene family remains an evolutionary mystery. In vivo expression analyses demonstrated up-regulation of 10/11 Leptospira genes identified in the attenuation screen, and profound in vivo, tissue-specific up-regulation by members of the paralogous gene family, suggesting a direct role in virulence and host-pathogen interactions. The pathogenomic experimental design here is generalizable as a functional systems biology approach to studying bacterial pathogenesis and virulence and should encourage similar experimental studies of other pathogens.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lehmann
authors.forename: Derrick E
authors.initials: DE
authors.lastname: Fouts
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Haft
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Cannella
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Ricaldi
authors.forename: Lauren
authors.initials: L
authors.lastname: Brinkac
authors.forename: Derek
authors.initials: D
authors.lastname: Harkins
authors.forename: Scott
authors.initials: S
authors.lastname: Durkin
authors.forename: Ravi
authors.initials: R
authors.lastname: Sanka
authors.forename: Granger
authors.initials: G
authors.lastname: Sutton
authors.forename: Angelo
authors.initials: A
authors.lastname: Moreno
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Vinetz
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthias
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics*; D001473:Bartonella / Q000235:genetics; D006224:Cricetinae; D004252:DNA Mutational Analysis; D015964:Gene Expression Regulation, Bacterial; D016680:Genome, Bacterial; D007921:Leptospira interrogans / Q000235:genetics* / Q000472:pathogenicity*; D007922:Leptospirosis / Q000382:microbiology*; D008647:Mesocricetus; D017422:Sequence Analysis, DNA; D037521:Virulence Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors